Holoptelea integrifolia/Ulmus integrifolia belongs to the family Ulmaceae. It is commonly known as Indian Elm Tree. The plant grows in India in the regions of Gujarat, Madhya Pradesh, Haridwar and in the Himalayas. Fruit is a samara (winged) nearly orbicular, 2 cms in diameter, on a slender stalk, wings membranous, tip bifid and lobes incurved. Fruits are plucked off the felled branches, cleaned and dried in the sun.
It is known by many local names, but more popularly as Kanju, Papri, Nemali etc. The seed oil is a good source of edible oil. Its leaves are commonly used along with a blend of other Ayurvedic herbs in herbal tea preparations for detoxification and rejuvenation. This herbal tea is also known to clear cellulite deposits and obliterates stretch marks that are fallen out of a weight problem. Holoptelea integrifolia was shown to exhibit antiviral activity in vitro assays and was recognized as one of the plant species useful to control air pollution.
Holoptelea integrifolia chemistry includes Steroids and triterpenoids; Triterpenoid constituents like amyrin, friedelin, epifriedelinol, friedel-1-en-3-one, lupeol, sitosterol, sitosterol-D-glucoside and stigmasterol in the petroleum ether extracts of the seeds; 2-alpha, 3-alpha-dihydroxyolean-12-en-28-oic acid isolated from the heartwood; two new triterpenoid fatty acid esters viz., Holoptelin A & B were also isolated.
Some of the non-patent literature of Holoptelea integrifolia is quoted below:
In India Holoptelea integrifolia has several medicinal properties and is used in conditions like rheumatism, to treat intestinal tumors, as an oxytocic in pregnant ladies, to treat common fevers. A combination of Holoptelea leaves with garlic and pepper is useful for treating Jaundice and the Stem bark acts as an anti-inflammatory agent specifically for eyes.
The methanol extract of bark exhibited significant radical scavenging activities and 5-Lipoxygenase inhibition activities. [M. Rama Rao et al, International Seminar on Medicinal Plants & Herbal Products [ISMPHP] Apr. 22, 2008; Tirupathi, India. URL: http://ismphpabstracts.blogspot.com/].
Bark and leaf paste are applied externally on the white patches of the skin. Leaves along with garlic are externally used to treat ringworm, eczema and cutaneous diseases. In Nepal, bark is externally used to relieve rheumatic swellings [Rajbhandari, M et al., 2001; J Ethnopharmacol, 74: 251-255].
The inventors have reported the antiobesity activity of Holoptelea integrifolia ameliorated through the inhibition of adipogenesis in the earlier PCT application (# PCT/IN2007/000356, filed Aug. 20, 2007). The effects of Holoptelea integrifolia on metabolic syndrome, atherosclerosis and diabetes have not been reported. The present invention thus involves a more significant and much effective metabolic marker amelioration shown by agents derived from Holoptelea integrifolia and their compositions for alleviating metabolic syndrome and other related diseases especially endothelial dysfunction, chronic kidney disease, atherosclerosis and diabetes.
Some of the patents related to the genus Ulmus and family Ulmaceae are quoted below:
Korean Patent KR20070070311 A relates to a composition for the prevention and treatment of Obesity and Hypercholesterolemia comprising extracts of natural products to reduce the number and size of adipocytes in the tissue, inhibit expression of genes associated with lipid synthesis including SREBP-1 (Sterol Response Element Binding Protein-1), FAS (Fatty Acid Synthase) and SCD-1 (Stearoyl CoA Desaturase) mRNA (messenger RNA) comprising the extracts of Semisulcospira libertine, sulfur fed duck, Ulmus macrocarpa Hance, pine pollen powder, Acer tegmentosum Maxim, bamboo salt, Artemesia capillaries, Platycodon Grandiflorum and Black bean in certain weight ratio.
Korean Patent KR10661478B1 relates to glycoprotein isolated from Ulmus davidiana nakai, and hepatoprotective and hypocholesterolemic pharmaceutical composition containing the glycoprotein.
U.S. Patent Publication US20060135444A1 and PCT Publications WO04045604A1, and WO04045605A1 relate to a nutritional composition suitable for reducing appetite, a method for the treatment and/or prevention of overweight and a method for the reduction of a mammalian appetite. The weight reduction and/or appetite reduction is achieved by administration of procyanidin and a flavonoid selected from the group consisting of chrysin, flavone, precursors of these flavonoids that are convertible into one of these flavonoids by gastrointestinal hydrolytic cleavage and mixtures thereof. In these publications the plant material or extract of plants like Pinus aristata, Prunus domestica, Ulmus sieboldiana etc., is used as a source of Flavonoid, preferably Chrysin.
Korean Patent KR2005003321A provides a method for manufacturing Ulmus davidiana juice which is used for treating inflammation, parasites, hypertension, cancer, diabetes and the like.
There is no prior art relating to the usage of Holoptelea integrifolia or its compositions for treating Metabolic Syndrome or for ameliorating metabolic marker proteins.
Metabolic Syndrome also known as Syndrome X/insulin resistance syndrome/Dysmetabolic Syndrome is a condition where in a group of diseased states which increase Atherosclerosis, Stroke and Diabetes. Metabolic Syndrome was first described as a cluster of interrelated common clinical disorders, including obesity, insulin resistance, glucose intolerance, hypertension and dyslipidemia.
A criteria for diagnosing Metabolic Syndrome was established by “The Adult Treatment Panel-III” (ATP-III) of the National Cholesterol Education Program in 2001. Five Criteria were selected by this Panel to identify individuals with Metabolic Syndrome including abdominal obesity, impaired fasting glucose, high triglyceride (TG), low HDL cholesterol (HDL-C) concentrations and increased blood pressure. Metabolic Syndrome is diagnosed, if any three of the components are present in an individual.
The definition set forth by the World Health Organization (WHO) includes diabetes or impaired glucose tolerance (IGT) and also lists thresholds for the risk factors of insulin resistance, raised arterial pressure, raised plasma triglycerides, central obesity, and microalbuminuria [Kelishadi R, Epidemiol Rev. 2007; 29: 62-76].
Obesity contributes to hypertension, high serum cholesterol, low HDL cholesterol, and hyperglycemia, and it otherwise associates with higher CVD risk. Abdominal obesity especially correlates with metabolic risk factors. Excess adipose tissue releases several metabolites that apparently exacerbate above risk factors. They include non-esterified fatty acids (NEFA), cytokines, PAI-1, and adiponectin [Scott M. G., et. al., Circulation 2004; 109; 433-438].
Hyper triglyceridemia and high density lipoprotein cholesterol (HDL-C), are two closely associated biochemical parameters that are commonly considered as syndrome criteria. Total cholesterol and low-density lipoprotein cholesterol (LDL-C) are considered to be significant risk factors for cardiovascular disease [Wilson P W F, et. al, Circulation 1998; 97: 1837-1847].
People with Metabolic Syndrome are at high risk of coronary heart disease, other diseases related to plaque buildups in artery walls (e.g., stroke and peripheral vascular disease) and type-2 diabetes.
The Metabolic Syndrome and most of its components were known to associate with a higher prevalence of calcified atherosclerotic plaque in the coronary arteries and abdominal aorta in white and African-American men and women.
Metabolic Syndrome has become a common affliction, affecting a quarter to a third of all adults, and its prevalence is rising, in parallel with increasing obesity and increasing aged population [Gerard, T. C., et. al, MJA 2006; 185: 445-449]. Hence, there is a need for the development of medicinal interventions for effective prevention, treatment and control of metabolic syndrome and diseased condition(s) associated with metabolic syndrome, especially those based on naturally agents or composition, as they believed to have minimum or negligible side effects.
A few prior art patents are quoted below which refer to the treatment and curing of Metabolic Syndrome.
PCT Publication WO08086403A1 describes the identification and isolation of chromones and novel chromone compositions from plant sources that are effective in enhancing adiponectin production by adipocytes and regulating genes involved in fatty acid biosynthesis. The invention also include methods for the prevention and treatment of a variety of diseases and conditions including, but not limited to insulin resistance, glucose intolerance, hyperglycemia, Metabolic Syndromes, dyslipidemia, and hypertriglyceridemia.
PCT Publication WO08093848A1 discloses a pharmaceutical product containing phosphatidylcholine derived from soybean for oral administration or for oral cavity application, a functional food and an oral composition which can prevent or ameliorate a disorder in the physical function induced by the increase in an inflammation marker, which can reduce the occurrence of Metabolic Syndrome or the risk of a disease and Metabolic Syndrome, and which can maintain or promote the healthy state.
As there is an urgent need for development of remedy for Metabolic Syndrome and the associated diseases, an effort was made by the inventors for finding a natural agent and composition which can be used for the effective control of Metabolic Syndrome in a safe manner and has minimized or has no side effects when compared to synthetic drugs available in the market.